BACKGROUND:Childhood obesity is a global public health crisis. Endocrine-disrupting chemicals (EDCs) - widespread pollutants that interfere with hormonal and metabolic systems - may contribute to excessive adiposity. The combined, long-term, and mechanistic effects of multi-class EDC mixtures remain unexplored. METHODS:We analyzed 1301 mother-child pairs from the Human Early Life Exposome (HELIX) project, spanning six European cohorts. Prenatal and childhood exposures to 45 EDCs across nine chemical classes were measured in maternal and child biospecimens. Thirty-six plasma proteins were quantified in childhood using targeted proteomic panels. Adiposity outcomes in childhood (6-11 years) and adolescence (12-18 years) included BMI z-scores, waist circumference, and body fat percentage. We applied penalized Lasso-type Bayesian Weighted Quantile Sum Regression to assess mixtures, a signed iterative random forest for interactions, and mediation analyses for biological pathways. RESULTS:Prenatal metal and organochlorine pesticide mixtures were associated with higher BMI z-scores in childhood and adolescence and 47-48 % higher odds of overweight. Prenatal PFAS exposure was associated with higher body-fat percentage in both periods. Childhood phenol and high-molecular-weight phthalate exposures were associated with higher adolescent zBMI, whereas parabens and persistent compounds showed inverse associations. Childhood metal exposures were associated with higher body-fat percentage and overweight odds. An inflammatory-metabolic protein pattern mediated ∼ 30 % of the prenatal metal-adolescent zBMI association. CONCLUSIONS:Early-life exposure to EDC mixtures may reprogram metabolic and inflammatory pathways, predisposing children to obesity that persists into adolescence. These findings provide mechanistic evidence linking chemical exposures to the global obesity epidemic and underscore the urgent need for policies preventing EDC exposure during critical developmental periods.

This study investigated the amount and proportion of unidentified organofluorine (UOF) in human serum and assessed short-term variability in exposure using extractable organofluorine (EOF) analysis and a fluorine mass balance approach. Serum samples were obtained from the well-characterized EuroMix cohort, comprising residents living in and around Oslo, Norway, collected between September 2016 and November 2017. Short-term intra-individual variability was evaluated using 72 paired serum samples collected 2-3 weeks apart. An extended target list of 64 PFAS, including trifluoroacetic acid (TFA), was applied to quantify identified and unidentified EOF. UOF accounted for up to 81% of EOF (median: 38%) in EuroMix samples. In 36% of paired samples, EOF concentrations varied by more than 25% over the 2-3-week interval, indicating the presence of compounds with relatively short biological half-lives. TFA was the most abundant individual PFAS detected, with median concentrations approximately twice those of PFOS. In a separate case study, serum samples from individuals using the fluorinated pharmaceutical Fluoxetine showed substantially elevated EOF and TFA concentrations (EOF: median 140 ng F/mL; TFA: median 27.7 ng/mL) compared with samples from individuals not using Fluoxetine (EOF: median < 8 ng F/mL; TFA: median 6.22 ng/mL). These findings indicate that fluorinated pharmaceuticals may contribute significantly to circulating EOF and TFA in humans. The large fraction of UOF and the widespread occurrence of TFA highlight the need to identify their sources relevant to human exposure. Together, these findings indicate that current PFAS including TFA biomonitoring approaches capture only a fraction (estimated to be 50%) of total human exposure to fluorinated substances and highlight the need to complement target analysis with fluorine mass balance approaches in future exposure assessment.

We are daily exposed to various environmental contaminants, including heavy metals, with suspected adverse health effects, and children's vulnerability is particularly concerning. Human biomonitoring is crucial for measuring these contaminants and essential elements in the body. The Norwegian Environmental Biobank (NEB), coordinated by the Norwegian Institute of Public Health, has collected biological samples (including blood and urine) and questionnaire data systematically since 2016. Identifying population subgroups at elevated risk is essential for implementing protective measures. This study aimed to describe concentrations of environmental contaminants and essential elements in Norwegian children and explored potential clustering among different contaminants. Additionally, we examined differences across groups defined by family socio-demographic factors. A total of 81 environmental contaminants were measured in urine, plasma, and whole blood from children aged 7-14 years participating in NEB. Twenty-six non-persistent and 24 persistent contaminants were quantified in ≥ 50 % of the samples, along with nine essential elements. Most children had contaminant levels below Human Biomonitoring Guidance Values (HBM-GVs). However, nearly all children had bisphenol A levels exceeding the updated tolerable daily intake set by the European Food Safety Authority (EFSA), and 30 % had blood concentrations of the four most common per- and polyfluoroalkyl substances (PFAS) exceeding EFSA's safe limits. Statistically significant differences in contaminant levels were observed between groups defined by sociodemographic variables such as sex, age, region, and degree of urbanization. Network analysis indicated clear clusters of several contaminants. This study shows that Norwegian children are exposed to a broad range of environmental contaminants, with levels similar to those reported in other studies from Europe and globally.

BACKGROUND:Identifying the primary determinants of exposure to contaminants such as poly- and perfluoroalkyl substances (PFAS) is essential for establishing efficient regulations. We aimed to identify determinants of serum PFAS during pregnancy, a sensitive exposure window. METHODS:This study relied on 450 pregnant women enrolled in a French cohort from 2014 to 2017. Socio-demographic, diet, water consumption and lifestyle factors were collected through questionnaires. Twenty-six PFAS were measured in maternal serum collected around 19 weeks of gestation (median). Multivariable linear or multinomial regressions were used to study the associations between determinants and individual PFAS, as well as with a three-category variable derived from clustering (categories representing women with the lowest (N = 163), moderate (N = 236) and highest (N = 51) concentration). RESULTS:Seven PFAS were quantified in 83 % or more of the samples, while the remaining PFAS were quantified in less than 20 %. The highest median concentrations were observed for PFOS (3.95 ng/mL), PFOA (1.02 ng/mL) and PFHxS (0.69 ng/mL). Maternal age was positively associated with all PFAS, and parous women had lower levels of PFOA, PFNA, PFHxS, PFOS and PFHpS than nulliparous. Fish and liver consumption were consistently and positively associated with PFUnDA, PFDA and PFNA. Use of hormonal contraception was found to be associated with a higher PFOA concentration, where a high level of education (5 years after high school) was associated with higher PFUnDA and PFDA levels. Multinomial models on clusters of PFAS exposures showed the same associations for maternal characteristics. CONCLUSION:Among the factors associated with higher PFAS concentrations in our cohort, those related to the consumption of specific food items may offer actionable levers to reduce exposure. Strengthened regulation should be prioritized over individual choices, as the latter can be strongly influenced by socio-economic status, potentially limiting the feasibility of individual dietary changes.

BACKGROUND:Maternal exposure to toxic and essential elements can be transferred to the fetus. Deciduous tooth dentine, formed prenatally, serves as a potential biomarker for fetal exposure. OBJECTIVE:To investigate the relationship between maternal blood Pb, Mn, Cu, Mo and Zn element concentrations and the corresponding child tooth dentine levels in mid pregnancy. A secondary objective explores the predictive value of maternal blood element concentrations for child dentine element levels for the same metals. METHODS:Early-life element concentrations were measured in maternal whole blood from the 2nd trimester and in child tooth dentine from 94 child-mother dyads enrolled in the Norwegian Mother, Father and Child Cohort Study (MoBa), The Norwegian Environmental Biobank (NEB) and the MoBaTooth biobank. The relationship between lead (Pb), manganese (Mn), copper (Cu), molybdenum (Mo) and zinc (Zn) in maternal blood and child dentine was examined using correlations and Receiver Operating Characteristic (ROC) curves. RESULTS:Maternal blood Pb concentration and child dentine Pb in 2nd trimester-average correlated strongly for both girls and boys (r = 0.58, p < 0.001 and r = 0.51, p < 0.001) and was able to predict child dentine Pb. Cu correlated negatively between mothers and boys (r = -0.35, p < 0.001), and with borderline significance for girls (r = -0.17, p = 0.058). For Mn, Mo and Zn the associations between maternal blood and child dentine were less clear and differed by child sex. CONCLUSION:Our analysis confirmed a strong association between maternal blood Pb concentration and child tooth dentine Pb. These findings offer a promising biomarker of early life exposure and may help to identify consequences of maternal exposure during pregnancy.

AIMS:The Joint Action project on Cancer and other Non-communicable Diseases (NCDs) prevention, Action on Health Determinants, includes a dedicated workstream on structural and population-level interventions. The overarching objective of this workstream is to strengthen the compliance, coherence, implementation and enforcement of evidence-based regulatory measures that support governmental efforts to reduce the burden of NCDs. METHODS:The workstream adopts a multi-method approach, informed by existing academic literature and previous European studies. Key methodologies include policy mapping, evidence reviews, behavioural assessments, policy impact modelling, and pilot testing. Governmental alcohol and tobacco policies will be evaluated using comparative policy scales, while the health and economic impacts of health taxation policies will be projected through and microsimulation modelling. Nutrient profile modelling and food composition databases will be developed to inform strategies for food reformulation. The effectiveness of labelling interventions will be examined. Tools for monitoring digital marketing exposure will be developed, and the impact of environmental policy impact will be assessed. EXPECTED RESULTS:The workstream is expected to deliver comprehensive policy analyses, demonstrate the potential impact of health taxation, propose harmonized nutrient profiling frameworks, assess the effectiveness of food and alcohol labelling practices and contribute to the development of cross-national structures for public food procurement. Additionally, it will provide guidance on the implementation of effective measures and evaluate divergences in national policy approaches across Europe. CONCLUSIONS:The workstream will generate actionable evidence and documentation to inform and support public policy processes, thereby contributing to reductions in the burden of preventable disease across the region.

Childhood obesity poses a significant public health challenge, yet the molecular intricacies underlying its pathobiology remain elusive. Leveraging extensive multi-omics profiling (methylome, miRNome, transcriptome, proteins and metabolites) and a rich phenotypic characterization across two parts of Europe within the population-based Human Early Life Exposome project, we unravel the molecular landscape of childhood obesity and associated metabolic dysfunction. Our integrative analysis uncovers three clusters of children defined by specific multi-omics profiles, one of which characterized not only by higher adiposity but also by a high degree of metabolic complications. This high-risk cluster exhibits a complex interplay across many biological pathways, predominantly underscored by inflammation-related cascades. Further, by incorporating comprehensive information from the environmental risk-scape of the critical pregnancy period, we identify pre-pregnancy body mass index and environmental pollutants like perfluorooctanoate and mercury as important determinants of the high-risk cluster. Overall, our work helps to identify potential risk factors for prevention and intervention strategies early in the life course aimed at mitigating obesity and its long-term health consequences. Obesity encompasses numerous interconnected pathological mechanisms. Here, the authors show that integrating multi-omics data uncovers distinct molecular profiles and prenatal factors linked to childhood obesity and metabolic dysfunction, providing insights for early prevention and intervention strategies.

Diet is a well-known source of environmental contaminants. This cross-sectional study explored children's dietary patterns and their association with contaminant exposure in the Norwegian Environmental Biobank. Parent-completed questionnaires provided data on children's frequency of intake of 36 foods and beverages, and socio-demographics. Several environmental contaminants were measured in urine, plasma, and whole blood from the children. Data were available for 658 children aged 7-14 years. Two dietary patterns, denoted "healthy" and "unhealthy," were identified using data driven factor analysis. We examined associations between child dietary patterns and contaminant concentrations using linear regression, adjusting for participant characteristics. The healthy pattern was positively associated with plasma perfluorononanoate (PFNA) concentration, whereas the unhealthy pattern was positively associated with urinary bisphenol A (BPA) concentration. Likelihood of exceeding health-based guidance value (HBM-GV) was examined using generalized linear model Poisson regression. The sum of the four most prevalent per- and polyfluoroalkyl substances (Ʃ4PFAS) increased with higher healthy pattern scores, with a relative risk (RR) of 1.18 (95 % CI: 1.06, 1.31) per standard deviation. Multiple regression analyses showed that egg and fish/shellfish consumption were associated with higher Ʃ4PFAS, with 4 % and 5 % higher concentrations per additional weekly serving, respectively (P < 0.001). For the sum of urinary di(isononyl)cyclohexane-1,2-dicarboxylate (ƩDINCH), 10 % higher concentration was observed per weekly serving of sweets/desserts. The urinary BPA concentration was 3 % higher per extra weekly serving of fruit juice (P = 0.001). These results highlight the need for societal measures to reduce contaminant exposure through food.

BACKGROUND:Prenatal exposure to poly- and perfluoroalkyl substances (PFAS) has been associated with lower birth weight or increased adiposity in adolescence. No study has investigated associations with longitudinal growth from conception to early childhood. We explored the association between maternal serum PFAS concentrations during pregnancy and child growth assessed repeatedly from the second trimester of pregnancy to 3 years of age. METHODS:In the SEPAGES cohort, for 450 pregnant women recruited before 19 gestational weeks in Grenoble (France), we measured 26 PFAS from non-fasting maternal serum samples (median gestational age at sampling: 19.4 weeks). Cluster-based analysis identified three PFAS exposure groups (low, moderate, high). Child growth parameters (weight, height, and head parameters) were measured at second and third trimesters (ultrasound examinations), at birth and until 3 years. Using a nonlinear mixed model, we predicted growth parameters and velocities at exactly 3 months and 3 years. RESULTS:Compared to children belonging to the low PFAS exposure group, those belonging to the high exposure group had higher head circumference during the second trimester (β [95 % CI] = 3.60 [1.49 to 5.72] mm) and at 3 years (39.85 [1.62 to 78.08] mm) as well as higher estimated fetal weight during the second trimester (15.85 [1.48 to 30.21] g) and BMI growth velocity at 3 years (9.66 [1.73 to 17.59] g/m2/month). PFAS concentrations were not associated with growth parameters at third trimester, birth and 3 months. CONCLUSIONS:In this prospective study, maternal serum PFAS concentrations were associated with some child growth parameters, potentially associated with increased risk of obesity in later-life.

Background: Animal studies have linked prenatal poly- and perfluoroalkyl substances (PFAS) exposures with impaired placental structure and function. In humans, only few studies have investigated such associations. Objective: We studied whether PFAS, individually and as a mixture, affected placental function. Methods: In 367 pregnant women, we quantified 13 PFAS in serum collected at 19.3 gestational weeks (median). Placental weight was recorded at delivery. Histological examination of placental tissues allowed estimation of vascular perfusion (percentage of villi with syncytial knots, capillary density, intervillous space) and placental aging (fibrin deposition, calcification). Associations between PFAS and each of these parameters were assessed using adjusted linear, logistic regressions and mixture modeling through cluster analysis and Bayesian kernel machine regression (BKMR). Results: PFHxPA quantification (yes versus no) was associated with an increase in the percentages of villi with syncytial knots ((3 = 6.0% [95% CI: 1.1; 11]) and reduced intervillous spaces ((3 = 4.7% [95% CI: 0.1; 9.3]). A similar pattern was observed with PFHpA. Isolated associations were observed between PFTrDA and percentages of villi with syncytial knots ((3 = 8.6% [95% CI: 2.2; 15]) and 6:2diPAP and capillary density ((3 =-17% [95% CI:- 30;- 4.6]). Cluster analysis suggested that women in the moderate-to-higher PFAS exposure group had on average lower placental weight ((3=-30 g [95% CI:- 56;- 4.3]), compared to those in the lower exposure group. Conclusions: Pregnancy PFAS levels were associated with placental parameters of fetal-maternal exchange, highlighting their broad physiological impacts.

Per- and polyfluoroalkyl substances (PFAS) are a group of endocrine-disrupting chemicals, however their effect on pubertal development remains largely unknown. In this cross-sectional study, we examined associations between PFAS exposure and pubertal timing in a cohort of 618 girls aged 6 to 16 years from the Bergen Growth Study 2 in Norway, 2016. Serum concentrations of 19 PFAS were measured, and pubertal development was assessed using several pubertal markers, including ultrasound-assessed breast development, Tanner staging, pubertal hormone levels, and age at menarche. We applied quantile g-computation, elastic net, and Bayesian regression to evaluate both combined and individual effects of PFAS exposure, in addition to single-pollutant analyses. Higher PFAS concentrations were significantly associated with later thelarche, pubarche, lower serum levels of luteinizing hormone, follicle-stimulating hormone, estrone, and estradiol, and later menarche. Among the PFAS analyzed, perfluorooctanesulfonic acid (PFOS) and perfluorodecanoic acid (PFDA) emerged as the key predictors of later pubertal markers. Our results indicate that PFAS exposure is associated with later puberty in girls.

Polychlorinated biphenyls (PCBs) are legacy contaminants that are enduring indoor environmental problems due to historical applications. Among residents living in PCB-contaminated and reference apartments, we compared the effectiveness of personal and environmental samples for determining exposure through associations with 14 serum PCBs and explored potential effects on thyroid biomarkers. Silicone wristband PCBs were strongly correlated with serum measurements, particularly for lower chlorinated PCBs (rs=0.59-0.82), and showed for the first time that wristbands are effective indicators of internal dose for PCBs. Similar correlations were observed for indoor air and dust, and hand wipes were significantly associated with serum for all congeners (rs=0.44-0.73). Stratified analyses, which accounted for some participant characteristics, demonstrated that significant relationships were specific to those living in contaminated apartments and most focused among lower chlorinated congeners. Here, residents had lived in their homes for many years (mean>10 years) and spent most of their time at home, due in part to being a majority aging population. As such, the four external exposure measures were strongly inter-correlated across the congeners. We also observed associations with free triiodothyronine (T3) and ratio between T3 and thyroxine (T4) in the exposed population. T3 and PCB-28 shared a significant, inverse dose-response relationship, with 13 and 17% decreases in T3 for the second and third serum PCB-28 tertiles, respectively. Our results suggest that any of the four sample types collected in this exposure scenario accurately pointed to elevated PCB exposure and that this exposure was associated with a change in thyroid hormone homeostasis.

Per- and polyfluoroalkyl substances (PFAS) are water-soluble chemicals of concern due to their persistence, ubiquity, and toxicity. We explored correlations between drinking water and blood PFAS levels in a subset of the mother-child Barcelona Life Study Cohort (BiSC), Barcelona, Spain (2021). For 105 study participants, we analyzed 35 PFAS in tap water (unfiltered and filtered) and 23 PFAS in 98 paired plasma samples during the 3rd trimester, using LC-MS/MS. Water consumption habits were ascertained at the third trimester through questionnaires. The majority of participants consumed bottled water (56.2%), 5/35 PFAS were detected in unfiltered tap water, 4/35 PFAS in activated carbon filtered tap water samples, and 14/23 PFAS in plasma samples. Our results showed that PFHpA at the observed concentrations in drinking water was significantly correlated with paired plasma levels (R = 0.2; p = 0.04).

Chemical exposures often occur in mixtures and exposures during pregnancy may lead to adverse effects on the fetal brain, potentially reducing lower cognitive abilities and fine motor function of the child. We investigated the association of motheŕs exposure to a mixture of chemicals during pregnancy (i.e., organochlorine compounds, per- and polyfluoroalkyl substances, phenols, phthalates, organophosphate pesticides) with cognitive abilties and fine motor function in their children. We studied 1097 mother-child pairs from five European cohorts participating in the Human Early Life Exposome study (HELIX). Measurement of 26 biomarkers of exposure to chemicals was performed on urine or blood samples of pregnant women (mean age 31 years). Cognitive abilities and fine motor function were assessed in their children (mean age 8 years) with a battery of computerized tests administered in person (Raveńs Coloured Progressive Matrices, Attention Network Test, N-back Test, Trail Making Test, Finger Tapping Test). We estimated the joint effect of prenatal exposure to chemicals on cognitive abilities and fine motor function using the quantile-based g-computation method, adjusting for sociodemographic characteristics. A quartile increase in all the chemicals in the overall mixture was associated with worse fine motor function, specifically lower scores in the Finger Tapping Test [-8.5 points, 95 % confidence interval (CI) -13.6 to -3.4; -14.5 points, 95 % CI -22.4 to -6.6, and -18.0 points, 95 % CI -28.6 to -7.4) for the second, third and fourth quartile of the overal mixture, respectively, when compared to the first quartile]. Organochlorine compounds, phthalates, and per- and polyfluoroalkyl substances contributed most to this association. We did not find a relationship with cognitive abilities. We conclude that exposure to chemical mixtures during pregnancy may influence neurodevelopment, impacting fine motor function of the offspring.